NEUROGLYCOPENIA: GENOTYPE-PHENOTYPE CORRELATION

描述（由申请人提供）：葡萄糖转运蛋白I型（Glut1）缺乏时（GlutlDS, OMIM 606777）会导致慢性神经性糖减少症和发育性脑病。这种缺陷是由GLUT1单倍不全引起的，它是一种常染色体显性遗传性状。该研究项目的长期目标是提高对发病机制的理解，提高对表型表现的认识，以及更好地治疗神经发育综合征。为了实现这些长期目标，我们提出了四个具体目标：(1)扩大我们对与GLUT1基因突变相关的glutds表型的理解；(2)将基因型致病性与表型严重程度联系起来；(3)在动物模型中复制人类疾病；(4)探讨glutds患者的替代治疗方案。研究设计和方法的发展是为了增加患者的招募；通过多学科方法评估表型变异性；并随时间对患者进行连续评估，以评估发育过程中的表型持久性以及性别对临床表现的影响。通过评估突变的性质以及由这些突变引起的动力学和结构-功能扰动，表型将与基因型相关。非洲爪蟾卵母细胞表达系统用于评估与错义突变相关的功能紊乱。GLUT1多态性将在glutds人群中确定，并与对照人群中类似多态性的存在/缺失进行比较。我们将建立转基因反义小鼠模型和基因靶向同源重组敲除小鼠模型，通过临床和神经病理学检查是否存在区域性脑损伤和神经元凋亡的证据。重点将放在确定受疾病影响最大的细胞类型上。细胞功能障碍和凋亡将通过从突变小鼠模型中获得的神经元和胶质培养物的体外研究来评估。将在小鼠模型中探索治疗机会，并应用于患者群体，评估生酮饮食和碳水化合物饮食的相对益处，以及使用未煮熟的玉米淀粉补充剂和二氮氧化合物治疗持续高血糖的优势。5小时口服葡萄糖耐量试验将被评估为一种可能的诊断工具，测量与短暂性高血糖相关的临床、神经心理和电图变化。

DESCRIPTION (provided by applicant): Glucose transporter protein Type I (Glut1), when deficient (GlutlDS, OMIM 606777), causes chronic neuroglycopenia and developmental encephalopathy. The deficiency results from GLUT1 haploinsufficiency, genetically transmitted as an autosomal dominant trait. The long-term objectives of this research project are improved understanding of the pathogenesis, increased awareness of the phenotypic presentations, and better treatment of the neurodevelopmental syndrome. Four specific aims are proposed to achieve these long-term objectives: (1) To expand our understanding of the GlutlDS phenotypes associated with GLUT1 gene mutations; (2) To correlate genotypic pathogenicity with phenotypic severity; (3) To replicate the human disease in an animal model; (4) To explore alternative treatment options for patients with GlutlDS. The research design and methods have been developed to increase recruitment of patients; to assess phenotypic variability by multi-disciplinary methods; and to serially evaluate patients over time to assess the phenotypic durability during development and the influences of gender on clinical expression. The phenotype will be correlated with the genotype by assessing the nature of the mutation and the kinetic and structure-function perturbations that result from these mutations. The Xenopus oocyte expression system is used to evaluate functional disturbances related to missense mutations. GLUT1 polymorphisms will be determined in the GlutlDS population and compared to the presence/absence of similar polymorphisms in a control population. A transgenic antisense mouse model and gene targeted homologous recombination knock-out mouse model will be examined clinically and neuropathologically for evidence of regional brain injury and neuronal apoptosis. Emphasis will be placed on establishing the cellular types most affected by the disease. Cellular dysfunction and apoptosis will be assessed by the in vitro study of neuronal and glial cultures derived from the mutant mouse models. Treatment opportunities will be explored in the mouse models and applied to the patient population assessing the relative benefits of a ketogenic diet and a carbohydrate diet, and the advantages of sustained hyperglycemia using uncooked cornstarch supplements and diazoxide. A 5-hour oral glucose tolerance test will be evaluated as a possible diagnostic tool measuring clinical, neuropsychological and electrographic changes associated with transient hyperglycemia.